Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/56—Ring systems containing three or more rings
  • C07D209/80—[b, c]- or [b, d]-condensed
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients

Definitions

• R is hydrogen or an optionally substituted hydrocarbon radical.
• R is hydrogen or an optionally substituted hydrocarbon radical.
• R and R together represent an 0X0 group or R is hydrogen and R is hydrogen or a free, etherified or esterified hydroxyl group or R is an optionally substituted hydrocarbon radical and R, a free, etherified or acylated hydroxyl group.
• X and X each is a hydrogen atom or may stand together for an oxo group, in the free form or in the form of their salts, e.g., the 1-phenyl-3-methyl-2,3,4,5-tetrahydro-1,4-methano-1H-3-benzazepine.
• the present invention relates to new benzazepincs. Especially it concerns 2:3:4:5-tetrahydro-l:4-methano- 1H-3-benzazepines having the following basic structure:
• substituents in the l-position are: alkyl radicals, for example, lower alkyl radicals such as methyl, ethyl, propyl or isopropyl radicals, straight-chain or branched butyl, pentyl, or hexyl radicals bound in any position, aryl or aralkyl radicals such as phenyl or phenyllower alkyl radicals, for example, benzylor 1- or 2- phenyl-ethyl radicals, which may be substituted in their aromatic nuclei by, for example, lower alkyl groups, for example, the above-mentioned, lower alkoxy groups, halogen atoms and/or trifiuoromethyl groups.
• Lower alkoxy 3,396,171 Patented Aug. 6, 1968 groups are, in particular, methoxy, ethoxy, propoxy or butoxy groups.
• the halogen atoms are, above all, chlorine or bromine atoms.
• the substituents in 3-position are, above all, saturated or unsaturated aliphatic, cycloalipha-tic or cycloaliphaticaliphatic hydrocarbon radicals or araliphatic or aromatic hydrocarbon radicals such as the above-mentioned alkyl, aryl or aralkyl radicals, or cycloalkyl or cycloalkyl-lower alkyl radicals, such as cyclopentyl, cycloheptyl radicals or cyclopropyl-, cyclobutyl-, cyclopentyl-, cyclohexylmethyl, -ethyl, -propyl or -butyl radicals or alkenyl radicals, such as allyl, methallyl or 3-methyl-2-butenyl radicals.
• the etherified hydroxyl groups are, above all, hydroxyl groups substituted by aliphatic or ar-aliphatic radicals.
• lower alkoxy groups for example, the above-mentioned alkoxy groups, lower alkenyloxy groups, for example, allyloxy, phenyllower alkoxy groups such as benzyloxy, lor Z-phenylethoxy groups in which the aromatic radicals may also contain substituents, for example, lower alkyl groups, lower alkoxy groups, halogen atoms or trifiuoromethyl groups.
• Esterified hydroxyl groups are, for example, hydroxyl groups esterified with inorganic acids, for example, hydrohalic acids, for example, chlorine or bromine atoms, or hydroxyl groups esterified with organic acids, especially acylated hydroxyl groups.
• inorganic acids for example, hydrohalic acids, for example, chlorine or bromine atoms
• organic acids especially acylated hydroxyl groups.
• Acylated hydroxyl groups are more especially carbamoyloxy groups, for example lower alkylcarbamoyloxy groups, such as methyl-, ethyl-, propylor butyl-carbamoyloxy groups or particularly lower alkanoyloxy groups, such as acetoxy, propionyloxy or butyryloxy groups or benzoyloxy groups.
• lower alkylcarbamoyloxy groups such as methyl-, ethyl-, propylor butyl-carbamoyloxy groups or particularly lower alkanoyloxy groups, such as acetoxy, propionyloxy or butyryloxy groups or benzoyloxy groups.
• substituents of the aromatic ring there come into consideration, for example, lower alkyl groups, lower alkoxy groups, hydroxy groups, acyloxy groups, halogen atoms, particularly those mentioned above, or trifiuoromethyl groups.
• the present invention provides a process for the manufacture of the new compounds, wherein a 4-oxo-1:2:3:4- tetrahydronaphthalene-l-carboxylic acid amide, which contains a halogen atom in 3-position, especially a chlorine, bromine or an iodine atom and whose amide nitrogen atom carries at least one hydrogen atom, is condensed intramolecularly and, if desired, substituents are introduced into the compounds thus obtained or substituents in the said compounds are modified or split off.
• a 4-oxo-1:2:3:4- tetrahydronaphthalene-l-carboxylic acid amide which contains a halogen atom in 3-position, especially a chlorine, bromine or an iodine atom and whose amide nitrogen atom carries at least one hydrogen atom
• the intramolecular condensation is advantageously carried out in the presence of basic condensing agents, for example, alkali hydroxides, for example, sodium or potassium hydroxide, alkali alcoholates, for example, sodium or potassium ethylate or methylate, and in the presence of solvents and/or diluents, for example, water or organic solvents, for example, alcohols, for example, lower alkanols such as methanol or ethanol, at room temperature, at a temperature below room temperature or at an elevated temperature.
• basic condensing agents for example, alkali hydroxides, for example, sodium or potassium hydroxide, alkali alcoholates, for example, sodium or potassium ethylate or methylate
• solvents and/or diluents for example, water or organic solvents, for example, alcohols, for example, lower alkanols such as methanol or ethanol
• Groups in the new products thus obtained may be modified or split off by known methods, or new groups may be introduced into the compound by known methods.
• compounds obtained having a hydrogen atom in 3-position and an oxo group in Z position may be substituted in 3-position, for example, by reaction with reactive esters of alcohols, for example, alkanols, alkenols, cycloalkanols, cycloalkyl-alkanols, or aralkanols.
• Reactive esters are, for example, esters with strong inorganic or organic acids, advantageously hydrohalic acids such as hydrochloric. hydrobramic or hydroiodic acid, or with aryl or alkyl sultonic acids such as benzene-, para-bromobenzeneor para-toluene-sulfonic acids.
• reaction is carried out in the customary manner at room temperature, at a temperature lower than room temperature or at an elevated temperature advantageously in the presence of basic condensing agents, especially strong bases such as alkali metal alcoholates, hydrides or amides and in the presence of solvents and/ or diluents.
• basic condensing agents especially strong bases such as alkali metal alcoholates, hydrides or amides and in the presence of solvents and/ or diluents.
• oxo groups in S-position may be reduced to hydroxyl groups by known methods, if desired, with the introduction, in S-position, of a hydrocarbon radical that may be substituted.
• Reduction of the oxo group is carried out in the customary manner, for example, by reduction with complex metal hydrides, for example, sodium boron hydride or lithium-aluminum hydride, or by hydrogen in the presence of a hydrogenation catalyst, for example, a platinum, nickel or copper catalyst such as platinum oxide, Raney nickel or copper chromite.
• the reaction is carried out at low temperature, room temperature or an elevated temperature in an open vessel or in a vessel under pressure, advantageously in the presence of a diluent and/ or solvent.
• the reaction is carried out, for example, with a reagent of the formula R M in which R represents a hydrocarbon radical that may be substituted and M represents the cation of lithium, or the group of the formula hal-Mg in which hal represents a halogen atom, for example, chlorine, bromine or iodine.
• R M represents a hydrocarbon radical that may be substituted
• M represents the cation of lithium
• hal-Mg in which hal represents a halogen atom, for example, chlorine, bromine or iodine.
• the reaction is carried out in the customary manner in the presence of an ether, for example, diethyl ether or tetra-hydrofuran.
• Catalytic reduction of the 0x0 group in S-position yields predominantly SIR-hydroxyl compounds.
• the oxo group in 5-position is reduced with complex light-metal hydrides, a mixture of the Sat-hydroxy compound and the SB-hydroxy compound is obtained.
• the 0x0 group is reduced with the introduction of a hydrocarbon radical, for example, by means of a Grignard compound, the compounds obtained are predominantly the 5,8-hydroxy compounds that contain the hydrocarbon radical in 5 a-position.
• a keto group in 2-position may be reduced in the usual manner to a methylene group. This reduction may be effected, for example, by lithium aluminum hydride.
• Compounds that are unsubstituted in 3-position and that do not contain an oxo group in 2-position may be substituted in the usual manner, for example by reaction with reactive esters of alcohols such as alkanols, cycloalkanols, cycloalkyl-alkanols, alkenols or aralkanols, for example, those mentioned above, or by reductive alkylation, that is to say, by reaction with an appropriate oxo compound and subsequent or simultaneous reduction.
• reactive esters of alcohols such as alkanols, cycloalkanols, cycloalkyl-alkanols, alkenols or aralkanols, for example, those mentioned above, or by reductive alkylation, that is to say, by reaction with an appropriate oxo compound and subsequent or simultaneous reduction.
• a further possibility for the substitution in the 3-position consists in reaction with an acylating agent and reducing the resulting 3-acyl compound, for example, with lithium-aluminumhydride.
• acylating agent a carboxylic acid halide or anhydride may be used, for example a pure or mixed anhydride or inner anhydride, such as a ketene.
• Free hydroxyl groups in the compounds obtained may be esterified or etherified.
• Etherification may be carried out, for example, by reaction with a reactive ester of an alcohol, for example, one of the above-mentioned esters, advantageously in the presence of a strong base, or by treatment with a trialkyloxonium fluoroborate, such as trimethyloxonium fiuoborate.
• Esterification of the hydroxyl groups in the 5, 6, 7, 8 or 9-position with organic acids may be carried out, for example, by reaction with the appropriate acid halide or anhydride, for example a pure or mixed anhydride or inner anhydride, such as a ketene or isocyanate.
• the appropriate acid halide or anhydride for example a pure or mixed anhydride or inner anhydride, such as a ketene or isocyanate.
• esterification of the hydroxy groups in the 5-position of compounds which contain in addition to the hydroxy group in the 5-position a hydrogen atom, with inorganic acids, for example with hydrohalic acids may be carried out, for example, by reaction with the appropriate acid, if desired in the presence of a catalyst, or by treatment with a halide of sulfur or phosphorus, such as thionyl chloride, phosphorus pentachloride, phosphorus oxychloride or phosphorus tribromide.
• acyl groups may be eliminated in a known manner by hydrolysis or by reduction with lithium aluminum hydride.
• the said halogen atom may be replaced by a hydrogen atom by hydrogenolysi or reduction, for example, with catalytically activated hydrogen or with complex light-metal hydrides.
• the latter may be converted into free hydroxy groups in the customary manner by hydrolysis, for example with the aid of hydrobromic or hydriodic acid
• hydrolysis for example with the aid of hydrobromic or hydriodic acid
• the said radical may be split off in a customary manner by hydrogenolysis, that is to say, by treatment with hydrogen in the presence of a hydrogenation catalyst, for example, a palladium catalyst.
• the procedure is to condense a 3-halogen-4- oxo-l22:3:4-tetrahydronaphthalene 1 carboxylic acid amide, whose amide nitrogen atom carries at least one hydrogen atom, intramolecularly, and to reduce the 0x0 group in S-position in the compound obtained to a hydroxyl group, if desired or required after substitution in 3-position, to reduce the keto group in Z-position to the methylene group and, if desired, to substitute the compounds obtained in 3-position and/or at the hydroxyl group in S-position, or to condense a 3-halogen-4-oxo- 1 :2 3 :4-tetrahydronaphthalene-l-carboxylic acid amide, whose amide nitrogen atom carries at least one hydrogen atom, intramolecularly and to reduce the 0x0 group in S-position in the compound thus obtained to
• a further advantageous reaction sequence is to condense a 3-halogen-4-oxo-1 :2: 3 4-tetrahydronaphthalenel-carboxylic acid amide, whose amide nitrogen atom carries at least one hydrogen atom, intramolecularly and to reduce the 0x0 group in S-position in the compound thus obtained to a hydroxyl group, if desired, after substitution in 3-position, to convert the hydroxyl group into a halogen atom, to convert the halogen atom into a hydrogen atom by reduction, to reduce the keto group in 2-position to a methylene group and, if desired, substitute the compounds obtained in 3-position.
• the new compounds which contain an asymmetric carbon atom in S-position, may be racemate mixtures, pure racemates or optical antipodes. If a carbon atom in S-position has two identical substituents, they may be pure racemates or optical antipodes.
• T'he substituent in 5-position, which is in syn-position to the methano bridge may be said to be in a a-position, and the substituent in anti-position to the methano bridge may be said to be in fi-position.
• racemate mixtures may be separated in known manner into the two stereoisomeric pure racemates, for example, by chromatography and/or fractional crystallization.
• Racemic products can also be resolved into the optical antipodes by known methods, for example, as follows: the racemic bases, dissolved in a suitable inert solvent, are reacted with an optically active acid, and the salts obtained are separated into the diasteroisomers, for example, by reason of their different solubilities, from which the antipodes of the new bases can be liberated by the action of an alkaline agent.
• the optically active acids generally used are d-tartaric acid and l-tartaric acid, diortho-toluyl tartaric acid, malic acid, mandelic acid, comphor-sulfonic acid and quinic acid.
• Optically active forms of the abovementioned compounds may also be obtained with the aid of biochemical methods. Separation can also be achieved by recrystallizing the pure racemate obtained from a suitable optically active solvent.
• the compounds unsubstituted in 2-position are obtained in the free form or in the form of their salts, which are also included in the invention, depending on the conditions under which the process is carried out and on the starting materials used.
• Salts that are obtained can be converted into the free bases in known manner, for example, by a treatment with alkalis or ion exchangers.
• Free bases that are obtained can be converted into salts by reaction with organic or inorganic acids, especially those that are suitable for the formation of therapeutically useful salts.
• Such acids are, for example, hydrohalic acids, sulfuric acids, phosphoric acids, nitric acid, perchloric acid; aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, for example, formic acid, acetic acid, propionic acid, succinic acid, glycollic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid and pyroracemic acid; phenylacetic acid, benzoic acid, para-aminobenzoic acid, anthranilic acid, para-hydroxybenzoic acid, salicylic acid, para-aminosalicylic acid, embonic acid, methane sulfonic acid, ethane sulfonic acid, hydroxyethane sulfonic acid, ethylene sulfonic acid; halogenbenzene sulfonic acid, toluene sulfonic acid, naphthalene
• salts of the new compounds for example, the picrates
• the free bases can also be used for purification of the free bases obtained; the free bases are converted into salts, the salts are separated and the bases are liberated from the salts.
• a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.
• the invention further includes any variant of the present process in which an intermediate product obtainable at any stage of the process is used as starting material and any remaining steps are carried out, or the process is discontinued at any stage thereof, or in which the starting material is formed under the reaction conditions, or in which the reaction components may be present in the form of their salts.
• a 4-oxo-l:2:3:4-tetrahydronaphthalenel-carboxylic acid amide can be halogenated in a basic medium, for example, in the presence of strong bases such as alkali hydroxides or alkali alcoholates to form the intermediate product 3-halogen-1:2:3:4-tetrahydronaphthalene-l-carboxylic acid amide, which is condensed intramolecularly by the action of the base that is present.
• the starting materials are known or can be obtained by methods in themselves known.
• the new compounds are valuable intermediate products suitable for use in the manufacture of pharmacologically active compounds.
• the compounds unsubstituted in 2-position defined above possess valuable pharmacological properties.
• they exhibit diuretic and saliuretic activity, which can be proved, for example, by tests on animals, for example, byoral administration to rats.
• they have an analgetic activity, for example in animal experiments, for example in the mouse, and are morphineantagonists, as has been shown in experimental animals, for example in the rabbit.
• they have a hypotensive effect.
• the aforesaid compounds may be used as diuretics, analgesics or hypotensives.
• R represents a lower alkyl radical or a phenyl or phenyl-lower-alkyl radical which may be substituted, for example, as indicated above, R represents a hydrogen atom or a lower alkyl radical or a phenyl loweralkyl radical, one of the radicals R and R especially R represents a hydrogen atom or a free, etherified or acylated hydroxyl group and the other radical represents a hydrogen atom or a lower alkyl radical or a phenyl radical that may be substituted, for example, as indicated above, and R represents a hydrogen atom or a lower alkyl radical or a lower alkoxy group or a halogen atom or a trifluoromethyl radical, and especially the compounds of the above formula in which R represents a lower alkyl radical, R represents a hydrogen atom or a lower alkyl radical, one of the radicals R and R especially R represents a
• methano-lH-3 -benzazepine 1-ethyl-3-methyl-5a-methyl-5 3-hydroxy-2 3 :4 S-tetrahydro-l :4-methano-1H-3-benzazepine and 1-ethyl-3-methyl-5tat-phenyl-5fi-hydroxy-8-methoxy- 2 :3 :4:5-tetrahydro-1 :4-methano-lH-3-benzazepine.
• R represents a lower alkyl radical or more especially an optionally substituted phenyl radical
• R represents a hydrogen atom, a lower alkyl radical, a phenyl-lower alkyl radical or more especially a lower alkenyl radical or a cycloalkyllower alkyl radical
• R and R represent two hydrogen atoms or a hydrogen atom and a free, lower alkylated, lower alkanoylated or lower alkylcarbarnoylated hydroxy group
• R represents a hydrogen atom, a lower alkyl radical, a lower alkoxy radical, a halogen atom a trifiuoromethyl group, a hydroxy group or a lower alkanoyloxy group.
• Especially active are the following:
• the pharmacologically active compounds can be used in the free form or in the form of their therapeutically acceptable salts for the manufacture of pharmaceutical preparations containing the said compounds in admixture or conjunction with organic or inorganic, solid or liquid pharmaceutical excipients suitable for enteral, parenteral or topical application.
• Suitable excipients are substances that do not react with the new compounds, for example, water, gelatine, lactose, starch, stearyl alcohol, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, propylene glycols, white petroleum jelly, cholesterol and other know medicinal excipients.
• the pharmaceutical preparations may be, for example, tablets, dragees, capsules, salves or creams, or in liquid form as solutions, suspensions or emulsions. They may be sterilized and/or contain assistants such as preserving, stabilizing, wetting or emulsifying agents, salts for regulating the osmotic pressure or bufiers. They may further contain other therapeutically valuable substances.
• the pharmaceutical preparations are prepared by conventional methods.
• the active compounds may also be used, for example, in the form of animal feedstufi or as additives for animal feedstufis.
• the usual extending agents and diluents are used or the usual feedstuffs.
• Example 2 4.6 grams (0.2 mol) of sodium are dissolved in 200 milliliters of absolute methanol. 14.8 grams (0.05 mol) of 1-ethyl-3 -bromo-4-oxo-1 :2 3 :4-tetrahydronaphthalenel-carboxylic acid amide are added in portions within a short time while stirring vigorously. During this process the temperature of the reaction mixture rises from 22 C. to 27 C. and the 1-ethyl-3-bromo-4-oxo-1:2:3:4-tetrahydronaphthalene-l-carboxylic acid amide dissolves rapidly.
• the 1-ethyl-3 -bromo-4-oxo-1 :2 3 :4-tetrahydronaphthalene-l-carboxylic acid amide used as starting material can be prepared as follows:
• Example 3 15.0 grams (0.65 mol) of sodium are dissolved in 500 milliliters of methanol. 99.3 grams (0.304 mol) of l-ethyl-3-bromo-4-oxo-7-methoxy- 122:3:4 tetrahydronaphthalene-l-carboxylic acid amide are added in portions at 18 C. in the course of 15 minutes while being stirred vigorously. The temperature of the reaction mixture rises to approximately 35 C. and, after a short time, the lethyl-3-bromo-4-oxo 7 methoxy 1:2:3z4 tetrahydronaphthalene-l-carboxylic acid amide dissolves completely.
• the batch is allowed to react for 1 hour at room temperature, and the 800 milliliters of water are allowed slowly to run into the flask.
• the 1-ethyl-2:5-dioxo-8-methoxy- 2 3 :4 S-tetrahydro-l :4-methanolH-benzazepine of the formula NH I F CzHr, CHaO precipitates out in the form of green-grey cubes melting at 156 to 158 C.
• the product is purified by recrystallization from ethyl acetate, whereby pale green crystals melting at 166 to 167 C. are obtained.
• the 1 ethyl 3 bromo 4 oxo-7-methoxy-1z2z3z4- tetrahydronaphthalene-l-carboxylic acid amide used as starting material can be prepared as follows:
• Example 4 17.6 grams (0.765 mol) of sodium are dissolved in 750 milliliters of absolute methanol. The solution is cooled to 15 C. and 92.7 grams (0.27 mol) of 1-phenyl-3-bromo- 4 oxo-l:2:3:4-tetrahydronaphthalene-l-carboxylic acid amide are added in portions in the course of 5 minutes, While stirring. After a short time, the bromine compound dissolves and the temperature rises to 28 to 30 C. Stirring is continued for a further 60 minutes, whereby the product begins to precipitate in the form of crystals. The reaction mixture is cooled to 0 C., and 200 milliliters of water are added.
• the crystalline product is isolated by suction filtration and washed well with water. Drying at 70 C. in a water-jet vacuum yields 1-phenyl-2z5-dioxo- 2:3 z4z5tetrahydro-l :4-methano-1H-3-benzazepine of the formula in the form of pale green crystals melting at 207 to 210 C. Colorless cubes melting at 209 to 211 C. are obtained after recrystallization from a mixture of chloroform and ether.
• the 1-phenyl-3-bromo-4-oxo-1 :2:3 :4-tetrahydronaphthalene-l-carboxylic acid amide used as starting material was prepared as follows:
• the filtrate is acidified with 5 N hydrochloric acid, whereby the 'y:y-diphenyl-y-cyanobutyric acid crystallizes out.
• the batch is cooled to 5 C., the acid is isolated by filtration and then washed well with water. After drying for 1 day at C. under a pressure of millimeters of mercury, the acid is obtained in the form of a colorless crystalline powder melting at 157 to 160 C. A test portion melts at 160 to 161 C. after recrystallization from a mixture of ethyl acetate and petroleum ether.
• the still moist filter cake is dissolved in 500 milliliters of chloroform, the chloroform solution is separated from the water and dried over sodium sulfate.
• the solvent has been evaporated off, 1 phenyl-4-oxo-1:2:3:4 tetrahydronaphthalene-l-carboxylic acid amide melting at to 186 C. remains.
• a test portion recrystallized from ethyl acetate yields colorless crystals melting at 187 C.
• Example 5 35.2 grams (0.1 mol) of l-ethyl-3-bromo-4-oxo- 1 2: 3 :4-tetrahydronaphthalene l-carboxylic acid-n-butylamide are dissolved in 150 milliliters of absolute methanol, and the solution is allowed to run into a solution of 9.2 grams (0.4 mol) of sodium in 150 milliliters of absolute methanol at 20 C. The solution is stirred for 1 hour at 20 C. and is then heated for a further hour at 50 C. The solution is cooled, rendered slightly acid by the addition to dilute hydrochloric acid, 200 milliliters of water are added and the solution is then extracted with choloroform.
• the oil that remains (25.2 grams) after the chloroform has been distilled off is dissolved in 100 milliliters of methanol, 35 milliliters of 2 N aqueous sodium hydroxide solution are added and the batch is allowed to stand for 2 hours at 25 C. 200 milliliters of water are added and the batch is extracted 3 times with 100 milliliters of chloroform each time.
• the united chloroform extracts are washed with -100 milliliters of water, dried over sodium sulfate and evaporated. The residue is chromatographed on 300 grams of alumina (containing 2% of water).
• Benzene elution yields 1-ethyl-2z5-dioxo- 1 1 3 (n-butyl)-2 3 :4: S-tetrahydro-l :4-methano-1H-3-benzazepine of the formula I N-om-om-ona in the form of a bottle green oil.
• the compound is further puri-fied by distillation in a high vacuum. This yields a yellow-green oil boiling at 145 to 160 C. under a pressure of 0.06 millimeter of mercury.
• the 1-ethyl-3-bromo-4-oxol-1 :2: 3 :4-tetrahydronaphthalene-l-carboxylic acid-n-butylamide used as starting material for the ring closure can be prepared as follows:
• This acid chloride is dissolved in 150 milliliters of methylene chloride, and a solution of 7.5 grams (0.103 mol) of n-butylamine in 50 milliliters of methylene chloride are added dropwise While cooling with ice. The batch is then boiled for 1 hour under reflux. The methylene chloride solution is cooled, extracted twice with 50 milliliters of ice-cold 2 N hydrochloric acid each time and then twice with the same amount of water. The organic phase is dried over sodium sulfate and evaporated. l-ethyl- 4-oxo-1 :2: 3 4-tetrahydronaphth'alene-1-carboxylic acidn-butylamide are obtained in the form of pale yellow oil.
• This amide is dissolved in 60 milliliters of glacial acetic acid, and then 16.0 grams (0:1 mol) of bromine are added dropwise at 20 C. The bromine is consumed immediately.
• the batch is evaporated in a water-jet vacuum at a temperature not exceeding 50 C. to yield l-ethyl-3- bromo-4-oxo-1 :2: 3 :4-tetrahydronaphthalene l-carboxylic acid-n butylamide in the form of a pale yellow oil that can be used directly for the ring closure with sodium methylate.
• Example 6 53.75 grams (0.25 mol) of l-ethyl-Z:-dioxo-2:3:4:5- tetrahydro-l:4-methano-1H-3-benzazepine are added to a suspension of grams (0.38 mol) of finely pulverized sodium amide in 500 milliliters of toluene and the whole is heated under reflux while stirring until the evolution of ammonia is practically finished (about 2 to 4 hours). The contents of the flask are cooled to 10 C., and 43 grams (0.38 mol) of methyl iodide are allowed to flow in all at once. The batch is stirred at room temperature for 4 hours, and the reaction is completed by boiling for 8 hours under reflux.
• the reaction mixture is cooled, milliliters of methanol are added dropwise and then, after a certain period of time, 200 milliliters of water are added.
• the toluene layer is separated in a separating funnel and again washed with milliliters of water.
• the aqueous phase is extracted once with methylene chloride, and the methylene chloride solution is Washed with water until the Washings run neutral.
• the united organic extracts are dried melting at 126 to 128 C. Recrystallization from ethyl acetate yields colorless cubes melting at 130 to 131 C.
• Example 7 30 grams (0.14 mol) of 1-ethyl-2:5-dioxo-2:3:4z5-tetrahydro-1:4-methano-lH-3-benzazepine are added to a suspension of 8.3 grams (0.213 mol) of sodium amide in 350 milliliters of absolute dioxane, and the whole is heated for 2 hours under reflux. The batch is cooled to 10 C., and 32.7 grams (0.21 mol) of ethyl iodide are allowed to flow in. The batch is then stirred for 5 hours at room temperature and subsequently for 10 hours at the boil.
• the excess sodium amide is decomposed with 50 milliliters of methanol and, after a short time, 500 milliliters of Water are added.
• the batch is then extracted with chloroform, and the chloroform extracts are Washed With Water. After drying over anhydrous sodium sulfate, the extracts are evaporated in a Water-jet vacuum, and the dark-colored oil that remain is distilled in a high vacuum.
• the 1:3-diethyl-2:5-dioxo-2:314:5- tetrahydro-l:4-methano-1H-3-benzazepine of the formula distilled as a colorless oil at to C. under a pressure of 0.1 millimeter of mercury.
• Example 8 When 30 grams (0.14 mol) of 1-ethyl-2z5-dioxo- 2: 3 :4 5-tetrahydro-1 4-methano- 1H-3 -benzazepine are reacted with 51 grams (0.277 mol) of n-butyl iodide in a manner analogous to that in Example 7, 1-ethyl-3-(n-butyl)-2:5-dioxo-2:314:5-tetrahydro 1:4-methano 1H 3- benzazepine of the formula is obtained in the form of a yellowish viscous oil boiling at 155 to C. under a pressure of 0.06 millimeter of mercury.
• Example 9 21.5 grams (0.1 mol) of 1-ethyl-2:5-dioxo-2:3:4:5- tetrahydro-1:4-methano-1H-3-benzazepine are added to a suspension of 5.9 grams (0.15 mol) of sodium amide in 250 milliliters of dioxane, and the Whole is stirred vigorously for 2 hours under reflux. The batch is cooled to 10 C., and 25.6 grams (0.15 mol) of benzylbromide are added dropwise. The batch is stirred for 2 hours at room temperature and then for 8 hours at the boil. Working up is then carried out in the manner described in Examples 7 and 8.
• Example 10 40 grams (0.152 mol) of 1-phenyl-2:5-dioxo-2:3:4: tetrahydro 1:4rnethano-1H-3-benzazepine and 8.9 grams (0.228 mol) of finely pulverized sodium amide are boiled for 3 hours under reflux in 900 milliliters of absolute dioxane. The contents of the flask are cooled to C., and 43.0 grams (0.3 mol) of methyliodide are added dropwise. The cooling ice is removed and the reaction mixture is stirred for 6 hours at room temperature. It is then :boiled for 12 hours under reflux.
• Example 11 30 grams (0.122 mol) of 1-ethyl-2:5-dioxo-8-rnethoxy- 2:3:4:5-tetrahydro-1:4-methano-1H-3 benzazepine and 7.15 grams (0.183 mol) of finely ground sodium amide are boiled under reflux for 4 hours in 500 milliliters of absolute dioxane. The batch is cooled to 10 C., and 26.1 grams (0.184 mol) of methyliodide are allowed to flow in. The batch is stirred for 4 hours at room temperature and is then heated for 10 hours at the boil.
• Example 12 22.9 grams (0.1 mol) of 1-ethyl-3-methyl-2:5-dioxo- 223:4:5 tetrahydro-l:4-methano-1H-3-benzazepine are dissolved in 250 milliliters of ethanol and then catalytically hydrogenated in the presence of 0.5 gram of platinum in the form of colorless crystals melting at 197 to 198 C., the yield being practically quantitative.
• Example 13 When 24.3 grams (0.1 mol) of 1:3-diethyl-2z5-dioxo- 2:3:4:5-tetrahydro-1:4 methano-lH-3-benzazepine are hydrogenated in ethanol using platinum oxide as catalyst in a manner analogous to that described in Example 12, 1:3 diethyl-2-oxo-5fi-hydrovy-2:3z4z5-tetrahydro- 1:4-methano-1H-3 -benzazepine of the formula is obtained. Recrystallization from a mixture of ethyl acetate and acetone yields colorless crystals melting at 194 to 196 C.
• Example 14 Catalytic hydrogenation of 1 ethyl-3-(n-butyl)-2:5- dioxo 2: 3 :4: S-tetrahydrod :4-me't-hano-1H-3-benzei1epine in fine spirit using platinum oxide by the method described in Example 12 produces 1-ethyl-2-oxo-3-(n-butyl)- 513 hydroxy-Z 3 :4: 5 -tetrahydro-1 4-methano-lH-3 -benzazepine of the formula in yield. When recrystallized from a mixture of ethylacetate and petroleum ether, the compound yields colorless flakes melting at 162 to 163 C.
• Example 15 Catalytic hydrogenation of 1-ethyl-2:5-dioxo-3-benzyl- 2:3 :4:5 tetrahydro 1:4 methano-1H-3-benzazepine in ethanol using platinum oxide by a method analogous to that described in Example 12 produces '1-ethyl-2-oxo-3- benzyl 5/8-hydroxy-2 3 :4:5-tetrahydro-1 :4-methano-1H- 3-benzazepine of the formula Recrystallization from a mixture of acetone and ether yields colorless crystals melting at 178 to 180 C.
• Example 16 21.5 grams (0.1 mol) of 1-ethyl-2:5-dioxo-2:3:4:5- tetrahydro-l:4-methano-lH-3-benzazepine are suspended in milliliters of methanol, and a solution of 3.8 grams (0.1 mol) of sodium boron hydride in 20 milliliters of water is added while agitating the flask.
• the 1-ethyl-2:5- dioxo 2:3:4:5 tetrahydro-l:4-methano-lH-3-benzazepine dissolves with vigorous evolution of foam.
• reaction mixture is diluted with 300 milli- 1 5 liters of water, whereby 1-ethyl 2 oxo 5 8 hydroxy- 2 3 :4: S-tetrahydro-l :4-methano-lH-3 -benzazepine of the formula NH Gila.
• this product contains less than 5% of the Sat-isomer.
• Example 17 24.5 grams (0.1 mol) of 1-ethyl-2:5-dioxo-8-methoxy- 2:3:4:5 tetrahydro 1:4-methano-1H-3-benzazepine are dissolved in 250 milliliters of fine spirit and catalytically hydrogenated at 38 C. under atmospheric pressure in in the form of colorless crystals melting at 170 to 171 C.
• Example 19 3.9 grams (0.16 mol) of magnesium parings that have been pretreated with iodine vapour are covered with 50 milliliters of absolute ether and converted into the Grignard compound by the addition of 23 grams (0.146 mol) of bromobenzene.
• the Grignard solution is added dropwise, while stirring vigorously and cooling with ice water, to a solution of 30.5 grams (0.133 mol) of l-ethyl- 2:5 dioxo 3 methyl-2:3:4:5-tetrahydro-1z4-methano- 1H-3-benzazepine in 130 milliliters of absolute tetrahydrofuran and 210 milliliters of absolute ether.
• Example 21 A Grignard solution prepared by reacting 4 grams (0.166 mol) of magnesium parings with 23.4 grams (0.165 mol) of methyl iodide in 5 0 milliliters of absolute ether is added dropwise and While stirring vigorously to a solution of 31.5 grams (0.137 mol) of 1-ethyl-2:5-dioxo- 3 methyl 2:3:4:5-tetrahydro-l:4-methano-1H-3-benzazepine in milliliters of absolute tetrahydrofuran and 200 milliliters of absolute ether, which solution is cooled with ice water. The whole is then boiled for 30 minutes under reflux.
• Example 22 By reacting a solution of methyl magnesium iodide, prepared from 2.1 grams (0.087 mol) of magnesium and 12.5 grams (0.088 mol) of methyl iodide in 50 milliliters of absolute ether, with 14.7 grams (0.06 mol) of 1:3- diethyl 2:5 dioxo-2z314:5-tetrahydro-l:4-methano-1H- 3-benzazepine in 50 milliliters of absolute tetrahydrofuran and 100 milliliters of absolute ether under the conditions described in Example 21, -18.9 grams of a crystalline, brownish product are obtained.
• Example 23 The reaction of l-ethyl-2:5-dioxo-3-(n-butyD-2:3:4:5- etrahydro-l:4-methano-lH-3-benzazepine with methyl magnesium iodide under the same conditions as those described in Example 22, yields l-ethyl-2-oxo-2-(n-butyl)- 5B hydroxy-5a-methyl-2 3 :4z5-tetrahydro-1 :4-methanolH-3-benzazepine of the formula ona L.
• Example 24 Reaction between methyl magnesium iodide and l ethyl 2:5 dioxo-3-benzyl-2z3:4:5-tetrahydro-1:4- methano-1H-3-benzazepine under the conditions described in Example 22 yields 1-ethyl-2-oxo-3-benzyl-5;3-hydroxy- 18 5a methyl 2:3 :4:5-tetrahydro-1 :4-methano-1H-3-benzazepine of the formula Recrystallization from ethyl acetate yields colorless crystals melting at 203 to 205 C.
• Example 25 is obtained in the form of colorless crystals melting at 243 to 245 C.
• Example 26 A solution of methyl magnesium iodide, prepared by reacting 2.1 grams (0.088 mol) of magnesium parings with 12.3 grams (0.087 mol) of methyl iodide in 30 milliliters of absolute ether is added dropwise, while cooling with ice, to a solution of 20 grams (0.072 mol) of 1- phenyl 2 5-dioxo-3-methyl-2 3 :4: 5 -tetrahydro-1 :4-methano-1H-3-benzazepine in 50 milliliters of absolute tetrahydrofuran and milliliters of absolute ether. The batch is then boiled under reflux for 30 minutes.
• Example 27 23.1 grams (0.1 mol) of 1-ethyl-2-oxo-3-methyl-5B- hydroxy 2 3 4 5 -tetrahydro-1 :4-methanolH-3-benzazepine are dissolved in milliliters of methylene chloride, 23.8 grams (0.2 mol) of thionyl chloride are added, and the whole is boiled for 6 hours under reflux. The clear solution is thoroughly evaporated in a water-jet vacuum. The residue is dissolved in 100 milliliters of ether and extracted twice with 30 milliliters of water. The solution in ether is dried over anhydrous sodium sulfate and directly filtered through a column containing 50 grams of alumina (containing 2% of water).
• Example 28 21.7 grams (0.1 mol) of a mixture comprising l-ethyl- 2 oxo-5a-hydroxy-2z3 14:5-tetrahydro-1 :4-methano-1H- 3-benzazepine and 1-ethyl-2-oxo-5fi-hydroxy-2:3:4z5-tetrahydro-1z4-methano-1H 3 benzazepine (of. Example 16), 80 milliliters of benzene and 20 milliliters of thionyl chloride are heated for 8 hours under reflux. The batch is evaporated in vacuo and the residue is digested in a mixture of ether and petroleum ether.
• l-ethyl-Z-oxo-S- chloro 2:3:415 tetrahydro-l:4-methano-1H-3-benzazepine is obtained in the form of colorless crystals melting at 160 to 180 C.
• the product is a mixture of the 5onchlorine compound and the S B-chlorine compound. This mixture can be catalytically dechlorinated directly (cf. Example 32).
• Example 29 30 grams (0.121 mol) of 1-ethyl-2-oxo-5B-hydroxy- 8 methoxy 2:3:425 tetrahydro 1:4 methano 1H- 3-benzazepine are dissolved in 500 milliliters of methylene chloride. 100 grams of anhydrous calcium chloride are added to the solution. A moderate stream of dry hydrogen chloride is introduced at 25 C. in the course of 3 hours while stirring vigorously. Subsequently, stirring is continued for 8 hours at room temperature. The insoluble inorganic salts are separated 01f by suction filtration, and washing is carried out thoroughly with chloroform. The filtrate is extracted twice with 50 milliliters of water each time, dried over anhydrous sodium sulfate and evaporated.
• Example 30 13.5 grams (0.055 mol) of 1-ethyl-2-oxo-5a-hydroxy- 8 methoxy 2:3:4:5 tetrahydro 1:4 methano 1H- 3-benzazepine are dissolved in 50 milliliters of benzene, and this solution, together with 13.0 grams (0.11 mol) of thionyl chloride, is heated for 2 hours under reflux at the boil. The batch is then evaporated thoroughly in a water-jet vacuum.
• the residue which comprises 20.0 grams of amber-colored oil having a pungent odor (its infra-red spectrum shows it to be the 5-chlorosulfinate), is dissolved in 200 milliliters of ether, and then 5 milliliters of water are cautiously added, while cooling with ice. This process is accompanied with the violent evolution of sulfur dioxide. At the same time, a product crystallizes out.
• the batch is allowed to stand for 2 hours at 25 C., whereupon the ether is evaporated off and the crystalline residue is dissolved in chloroform. The solution is extracted twice with water, dried over anhydrous sodium sulfate, and evaporated.
• Recrystallization from a mixture of chloroform and petroleum ether yields colorless crystals melting at 170 to 171 C. According to their infrared spectrum and mixed melting point, they are identical with the product obtained in Example 29, which melts at 170 to 171 C.
• the catalyst is separated ofi by filtration, the filtration is evaporated, and the residue is dissolved in ether.
• the solution is extracted with aqueous sodium bicarbonate solution and then with water, and the ethereal solution is dried over anhydrous sodium sulfate.
• Example 32 11.75 grams (0.05 mol) of a mixture of the stereoisomeric l-ethyl-2-oxo-5-chloro-2:3 :4:5 tetrahydro-1z4- methano-lH-3-benzazepines are dissolved in 200 milliliters of ethanol, and hydrogenated at 40 C. under atmospheric pressure in the presence of 1 gram of 10% palladium carbon catalyst. If hydrogenation ceases prematurely, the contaminated catalyst must be replaced. After 1110 milliliters (99% of the amount required by' theory) of hydrogen has been taken up, the batch is separated from the catalyst by filtration and evaporated in a Water-jet vacuum. 10 grams of oil are obtained which yields 1-ethyl-2-oxo-2 3 :4 5 -tetrahydro-1 :4-methano-1H- 3-benzazepine of the formula -NH L.
• Example 33 21.7 grams (0.1 mol) of l-ethyl-2-oxo-5 8-hydroxy- 2:3:4:5-tetrahydro l :4 methano 1H-3-benzazepine are dissolved in 300 milliliters of absolute tetrahydrofuran, and the solution is added dropwise in the course of 30 minutes and while stirring to a suspension of 8 grams (0.2 mol) of lithium-aluminum hydride in 200 milliliters of absolute tetrahydrofuran, which suspension is boiling under reflux. The reaction mixture is then boiled under reflux for a further 10 hours.
• the base that precipitates is extracted in the usual manner with methylene chloride, and l-ethyl-Sfl-hydroxy-Z:3:4:5- tetrahydro-l:4-methano-lH-3-benzazepine of the formula HOH on; Alli H' .cnisoi melting at 240 to 243 C. (with decomposition) crystallizes out.
• a test portion recrystallized from a mixture of acetone, ethanol and ether yields crystals melting at 241 to 243 C. (with decomposition).
• the above salt can easily be split by acid hydrolysis to yield the starting amine.
• Example 34 When 23.1 grams (0.1 mol) of 1-ethyl-2-oxo-3-methyl- 5,8 hydroxy 2:3:4:5 tetrahydro 1:4 methano 1H- 3-benzazepine are reduced with grams (0.25 mol) of lithium-aluminum hydride in tetrahydrofuran in the manner described in Example 33, l-ethyl-3-methyl-5 3-hydroxy 2:3:4:5 tetrahydro 1:4 methano 1H 3- benzazepine of the formula is obtained in the form of a colorless oil.
• the hydrochloride crystallizes from a mixture of acetone and isopropanol in the form of colorless, moderately hygroscopic flakes melting at 180 to 181 C.
• tetrahydro-1:4-methano-1H-3-benzazepine is reduced with lithium-aluminum hydride in tetrahydrofuran by the method described in Example 33, 1:3-diethyl-5fi-hydroxy- 2: 3 24:5-tetrahydro-1 :4-methano-1H-3-benzazepine of the formula Example 36 Reduction of 1-ethyl-2-oxo-3-(n-butyl)-5,3-hydroxy-2: 3 :4z5-tetrahydro-1 :4-methano-1H-3-benzazepine with lithium-aluminum hydride in tetrahydrofuran by the process described in Example 33 produces 1-ethyl-3-(n-butyl)-5,8-
• the hydrochloride crystallizes from acetone in the form of colorless flakes melting at 219 to 220 C.
• Example 37 Reduction of 1-ethyl-2-oxo3-benzyl-5fl-hydroxy-2 3 4: S-tetrahydro-l :4-methano-1H-3-benzazepine with lithium-aluminum hydride in tetrahydrofuran by the process described in Example 33 yields 1-ethyl-3-benzyl-5B-hydroxy 2:3:4:5 tetrahydro 1:4 methano 1H 3- benzazepine of the formula HO H in the form of a viscous oil which can be directly converted into the hydrochloride.
• the hydrochloride crystallizes from acetone in the form of colorless crystals melting at 244 to 246 C.
• Example 38 A solution of 24.5 grams (0.1 mol) of 1-ethyl-2-oxo- 3:5 dimethyl 55 hydroxy 2:3:4:5 tetrahydro 1:4- rnethano-lH-3-benzazepine in 300 milliliters of absolute tetrahydrofuran is added dropwise in the course of 1 hour to a boiling suspension of 8 grams (0.2 mol) of lithiumaluminum hydride in milliliters of absolute tetrahydrofuran while the said suspension is being vigorously agitated, and then boiling is continued for 10 hours under refiux.
• Example 39 60.2 grams (0.196 mol) of 1-ethyl-2-oxo-3-methyl-5flhydroxy 50c phenyl 2:3:4:5 tetrahydro 1:4 methano-1H-3-benzazepine are dissolved in 250 milliliters of absolute tetrahydrofuran, and the solution is added drop- Wise to a boiling suspension of 21 grams (0.53 mole) of lithium-aluminum hydride in 200 milliliters of absolute tetrahydrofuran. After boiling for 10 hours under reflux, working up is carried out in the manner described in Example 38.
• the basic crude product is not taken up in hydrochloric acid however, but is dissolved in 100 milliliters of a 1:1 benzene/methylene chloride mixture, absorbed on an alumina column (containing 2% of water) and then exhaustively eluted with the same solvent mixture. An oil remains after the eluting agent has been evaporated off. 200 milliliters of petroleum ether are quickly added and the product is allowed to crystallize out. l-ethyl 3 methyl 5 3 hydroxy 5oz phenyl 2:3:4z5- tetrahydro-l:4-methano-1H-3-benzazepine of the formula HOQ is thus obtained in the form of colorless granular crystals melting at 118 to 119 C.
• Example 40 Reduction of 1-ethyl-2-oxo-3-methyl-5fi-hydroxy-5a- (para methoxy phenyl) 223:4:5 tetrahydro 1:4- methano-lH-3-benzazepine with lithium-aluminum hydride by the process described in Example 39, yields l-ethyl 3 methyl 5B hydroxy 5oz (para methoxyphenyl) 223:4:5 tetrahydro 1:4 methano 1H 3- benzazepine of the formula in the form of colorless flakes. After recrystallization from a mixture of benzene and petroleum ether, the compound melts at 105 to 106 C.
• the hydrochloride melts at 238 to 240 C. (with decomposition).
• Example 41 Reduction of 1:3-diethyl-2-oxo-5fl-hydroxy-5a-methyl- 2:3:4:5 tetrahydro 1:4 methano 1H 3 benzazepine with lithium-aluminum hydride by the process described in Example 38 yields l:3-diethyl-5 3-hydroxy-Set-methyl- 2:3 z4z5-tetrahydro-1 :4-methano-lH-3-benzazepine of the formula in the form of a colorless oil.
• the hydrochloride which is produced in the customary manner, melts at 208 to 209 C. after recrystallization from a mixture of acetone and ether.
• Example 42 Reduction of 1-ethyl-2-oxo-3-(n-butyD-Sfi-hydroxy-Samethyl 2:3:415 tetrahydro 1:4 methano 1H 3- benzazepine by the method described in Example 38 yields 1 ethyl 3 (n butyl) 515' hydroxy 5a methyl 223:4:5 tetrahydro 1:4 methano -1H 3 benzazepine of the formula in the form of a yellow viscous oil.
• the hydrochloride is obtained in the form of colorless crystals melting at 225 to 227 C. after recrystallization from a mixture of acetone and ethyl acetate.
• Example 43 Reduction of 1-ethyl-2-oxo-3-benzyl-5fi-hydroxy 5amethyl 2:3:425 tetrahydro 1:4 methane 1H 3- benzazepine with lithium-aluminum hydride by the process described in Example 38 yields 1-ethyl-3-benzyl-5fi-hydroxy 50c methyl 2:3:4:5 tetrahydro 1:4 methano- 1H-3-benzazepine of the formula HO CH3 in the form of a pale yellow viscous oil.
• the hydrochloride is obtained in the form of a colorless crystal powder melting at 231 to 233 C.
• Example 44 is obtained in the form of a colorless oil.
• the hydrochloride is obtained in the form of a colorless crystal powder melting at 147 to 148 C.
• Example 45 A solution of 14.8 grams (0.056 mol) of 1-ethy1-2-oxo- 5-chloro-8-methoxy 2:3 :4:5 tetrahydro 1:4-methanolH-3-benzazepine in 300 milliliters of absolute tetrahydrofuran is added dropwise to a boiling suspension of 7.5 grams (0.19 mol) of lithium-aluminum hydride in 200 milliliters of absolute tetrahydrofuran. After boiling for 15 hours under reflux, working up is carried out in the manner described in Example 38.
• the hydrochloride crystallizes from a mixture of isopropanol and ether in the form of colorless needles melting at 171 to 172 C.
• Example 46 11.9 grams (0.055 mol) of 1-ethyl-8-methoxy2:3:4:5- tetrahydro-l:4-methano-1H-3-benzazepine are dissolved in 10 milliliters of formic acid of 98% strength, 4.5 milliliters (0.06 mol) of aqueous formalin (40% by volume) are added, and the whole is heated for 4 hours on a boiling Water bath. The batch is evaporated in vacuo, the residue is taken up in 50 milliliters of 2 N hydrochloric acid, filtered through active carbon, and the filtrate is rendered alkaline with N sodium hydroxide solution.
• Example 47 A solution of 26.0 grams (0.077 mol) of 1-ethyl-2-oxo- 3-methyl 5B hydroxy 5a phenyl-8-methoxy-2:3 :425- tetrahydro-l:4-methano-lH-3-benzazepine in 650 milliliters of absolute tetrahydrofuran is added dropwise in the course of 1 hour to a boiling suspension of 7.3 grams (0.187 mol) of lithium-aluminum hydride in 100 milliliters of absolute tetrahydrofuran. Boiling is continued for a further 10 hours under reflux and then Working up is carried out in the manner described in Example 38.
• the base is taken up in 100 milliliters of acetone and neutralized with a 2 N solution of hydrogen chloride in ethyl acetate.
• the hydrochloride crystallizes out in the form of colorless crystals melting at 229 to 230 C.
• Example 48 19.0 grams (0.065 mol) of l-phenyl-2-oxo-3z5u-dimethyl 5/3 hydroxy 2:3:425-tetrahydro-1:4-methanolH-3-benzazepine are dissolved in 500 milliliters of absolute tetrahydrofuran, and the solution is added dropwise in the course of 30 minutes to a boiling suspension of 6.2 rams (0.16 mol) of lithium-aluminum hydride in 100 milliliters of absolute tetrahydrofuran. Boiling is carried out under reflux for hours and then Working up is carried out in the manner described in Example 38.
• Example 49 A solution of 8.3 grams (0.032 mol) of l-ethyl-ZzS-diox-o 3- (n-butyl -2: 3 :4 S-tetrahydro-l :4-methano-lH-3- benzazepine in milliliters of absolute tetrahydrofuran is added dropwise to a suspension of 3.1 grams (0.08 mol) of lithium-aluminum hydride in 100 milliliters of absolute tetrahydrofuran, which suspension is being boiled under reflux. Boiling is continued for a further 20 hours.
• Example 38 Working up in the manner descrbied in Example 38 yields 1- ethyl 3 (n-buyt1)-5,8-hydr0xy-2:3z4z5-tetrahydro-lz4- methano-lH-3-benzazepine of the formula CZHE in the form of a pale yellow oil boiling at 124 to 128 C. under a pressure of 0.09 millimeter of mercury.
• the hydrochloride melts at 219 to 220 C. and is identical with the hydrochloride indicated in Example 36 and having the same melting point.
• Example 50 6.5 grams (0.022 mol) of 1-ethyl-3-(n-butyD-SB-hydroxy 2:3:4z5 tetrahydro-l:4-methano-lH-3-benzazepine hydrochloride. 40 milliliters of acetic anhydride and 5 milliliters of an hydrous pyridine are heated for 1 hour on a Water bath. A clear solution is quickly obtained. The batch is evaporated in a Water-jet vacuum, the residue is taken up in chloroform and then extracted successively With sodium bicarbonate and water.
• tetrahydro-l :4-methano-lH-3-benzazepine are dissolved in mols of absolute tetrahydrofuran, and the solution is added dropwise to a boiling suspension of 8 grams (0.2 mol) of lithium-aluminum hydride in 150 milliliters of absolute tetrahydrofuran. After boiling for 10 hours under reflux, working up is carried out in the manner described in Example 38.
• 1-ethyl-3-methyl-2z324:5-tetrahydro-1:4- methano-1H-3-benzazepine of the formula is thus obtained in the form of a colorless oil boiling at 75 to 82 C. under a pressure of 0.04 millimeter of mercury.
• the hydrochloride melts at 142 to 143 C.
• Example 52 25 grams (0.1 mol) of 1-ethyl-2-oxo-3-methyl-5-chloro- 2:3 :4 -tetrahydro- 1 4methano-1H-3 benzazepine are dis solved in 250 milliliters of absolute tetrahydrofuran, and the solution is added dropwise in the course of 1 hour to a boiling suspension of grams (0.25 mol) of lithiumaluminum hydride in 300 milliliters of absolute tetrahydrofuran. Boiling is continued under reflux for hours and then working up is carried out in the manner described in Example 38.
• Example 5 A solution of 20.1 grams (0.1 mol) of 1-ethyl-2-oxo- 2: 3 :4 S-tetrahydro-l 4-methano-1H-3-benzazepine in 200 milliliters of absolute tetrahydrofuran is added dropwise in the course of minutes to a boiling suspension of 6 grams (0.15 mol) of lithium-aluminum hydride in 200 milliliters of absolute tetrahydrofuran.
• the hydrochloride crystallizes from a mixture of isopropanol and ether in the form of colorless crystals melting at 191 to 192 C.
• Example 54 8.0 grams (0.0233 mol) of 1-ethyl-3-benzyl-5B-hydroxy 5a methyl 2:3 :4: 5 tetrahydro 1:4 methano- 1H-3-benzazepine hydrochloride are dissolved in 250 milliliters of rectified spirit and then catalytically debenzylated at 27 C. under atmospheric pressure in the presence of 1 gram of 10% palladium carbon. Hydrogenation ceases after 1 mol of hydrogen (522 milliliters) has been taken up. The catalyst is filtered off, the solvent is evaporated, and the residue is recrystallized from a mixture of ethanol and ether.
• Example 55 formula HO H in the form of greenish crystals melting at 205 C.
• the infra-red spectrum of the compound shows a broad band at about 3n (associated hydroxyl bands) and a sharp band at 6.01 (lactam grouping, hydrogen bridge between the 5fl-hydroxyl group and the nitrogen of the lactam).
• Example 56 2.63 grams (0.01 mol) of 1-phenyl-2:5-dioxo-2:3:4z5- tetrahydro-1:4-methano-1H-3-benzazepine are dissolved in 50 milliliters of methanol, and a solution of 0.78 gram (0.02 mol) of sodium boron hydride in 3 milliliters of water is added. When the evolution of hydrogen has subsided, the batch is slowly diluted with a total amount of milliliters of water, whereby 1.32 grams (50%) of a colorless product melting at 215 to 225 C. crystallizes out.
• Example 57 26.5 grams (0.1 mol) of 1-phenyl-2-oxo-5B-hydroxy- 2:3:4:5 tetrahydro 1:4 methano 1H 3 benzazepine, 30 milliliters of thionyl chloride and 50 milliliters of methylene chloride are boiled under reflux for 6 hours. The clear solution is evaporated, the residue is taken up in 100 milliliters of ether and allowed to stand in an open vessel. After a short time, sulfur dioxide begins to develop vigorously and the solution heats up to the boil. Colorless crystals precipitate out. After the evolution of sulfur dioxide has subsided, the batch is cooled to C. and the product is filtered off.
• the catalyst is filtered ofif while the batch is still hot.
• the palladium carbon is extracted 3 times with chloroform at the boil and under reflux. Evaporation of the combined filtrates yields 1- phenyl 2 oxo 223:4:5 tetrahydro 1:4 methano- 1H-3-benzazepine of the formula in the form of colorless crystals melting at 230 to 235 C.
• One recrystallization from isopropanol yields colorless prisms melting at 235 to 236 C.
• Example 59 When 3.4 grams (0.012 mol) of 1-phenyl-2-oxo-5- chloro 2:3:4:5 tetrahydro 1:4 methano 1H 3- benzazepine (stereoisomer II melting at 185 to 186 C.) are hydrogenated with 1.5 grams of 10% palladium carbon, the catalyst being added in 3 portions, a total of 280 milliliters (0.0125 mol) of hydrogen are taken up in the course of hours (hydrogenation carried out at 45 C. under atmospheric pressure).
• Example 60 A solution of 8.7 grams (0.035 mol) of l-phenyl-Z-oxo- 2: 3 :4 5 -tetrahydro-1 :4-methano-1H-3-benzazepine in 400 milliliters of absolute tetrahydrofuran is added dropwise in the course of 1 hour to a suspension of 4 grams (0.1 mol) of lithium-aluminum hydride in milliliters of absolute tetrahydrofuran, which suspension is being boiled under reflux. Boiling is continued under reflux for a further 8 hours and while stirring.
• Example 61 6.0 grams (0.15 mol) of finely ground sodium amide are added to 24.9 grams (0.1 mol) of 1-phenyl-2-oxo- 2:3 :4:5-tetrahydro-1 :4-methano-1H-3-benzazepine in 500 milliliters of absolute dioxane, and the whole is boiled under reflux for 2 hours. The reaction mixture is cooled to 10 C. and 20.2 grams (0.15 mol) of methyl iodide are allowed to run in one portion. The reaction mixture is stirred for 5 hours at 20 C. and is then boiled under reflux for 10 hours.
• Example 62 10.5 grams (0.038 mol) of l-phenyl-2z5-dioxo-3- methyl 2:3:425 tetrahydro-1:4-methano-1H-3-benzazepine are hydrogenated catalytically in 250 milliliters of rectified spirit at 36 C. under atmospheric pressure in the presence of 0.5 gram of platinum oxide. 878 milliliters (0.039 mol) of hydrogen are taken up in the course of 30 minutes. A portion of the product crystallizes out during this process. 200 milliliters of chloroform are added, the
• the hydrogenation proceeds practically stereospecifically.
• Example 63 10.5 grams of 1-phenyl-2-oxo-3-methyl-5/3-hydroxy- 2z3z4z5-tetrahydro 1:4 methano-1H-3-benzazepine, 20 milliliters of thionyl chloride and 50 milliliters of methylene chloride are boiled under reflux for 6 hours. The batch is evaporated to dryness, the residue is dissolved in a small amount of ethyl acetate, a small amount of ether is added and the solution is allowed to stand overnight at 0 C. in an open reaction vessel.
• Example 64 2.98 grams (0.01 mol) of 1-phenyl-2-oxo-3-methyl-5- chloro 2:3:425 tetrahydro-l:4-methano-1H-3-benzazepine are hydrogenated catalytically in 100 milliliters of ethanol at 40 C. under atmospheric pressure in the presence of 0.5 gram of palladium carbon. 253 milliliters (0.0113 mol) of hydrogen are taken up in the course of 2 hours; hydrogenation then ceases. The batch is filtered, the catalyst is extracted at the boil 3 times with 10 milliliters of chloroform, and the combined filtrates are evaporated.
• the hydrochloride of this product after being recrystallized from ethanol+ether, melts at 225 to 228 C. with evolution of gas.
• Example 66 12 g. of finely ground potassium carbonate are added to a solution of 8.0 g. (31.5 mmols) of l-phenyl-S/S-hydroxy 2: 3 :4 5 Jetrahydro-l :4-methano-1H-3-benzazepine in 200 ml. of isopropanol, and the mixture cooled to 0 to 5 C. While stirring and cooling with ice water, 4.0 g. (66 mmols) of allyl bromide are added dropwise, and stirring continued overnight at 20 C. The inorganic salts are filtered o& with suction, the filtrate evaporated under a water-jet vacuum, and the residue dissolved in methylene chloride.
• Example 67 10.4 g. of the crude 1-phenyl-3-allyl-5p-hydroxy-2:3:4: 5 tetrahydro-l:4-methano-1H-benzazepine obtained according to Example 66 are heated on a water bath for 12 hours with 5 m1. of anhydrous pyridine and 20 m1. of acetic anhydride.
• Example 68 13.2 g. (0.126 mol) of cyclopropanecarboxylic acid chloride are added dropwise, While cooling, to 13.8 g. (0.055 mol) of 1-phenyl-5,8-hydroxy-2:3:4z5-tetrahydro- 1:4 methano-1H-3-benzazepine and 11.1 g. (0.11 mol) of triethylamine in 200 ml. of methylene chloride. The batch is left to itself for 12 hours at room temperature, then heated to the boil for 3 hours. After cooling, it is extracted with aqueous sodium bicarbonate, then with water, and the methylene chloride solution is dried over sodium sulfate.
• Example 69 A solution of 18.0 g. of the crude 1-phenyl-3-(cyclopropylmethyl) SB-hydroxy-Z: 3 :4 5 -tetrahydro-1 :4-methano-1H-3-benzazepine in ml. of pyridine and 200 ml. of methylene chloride is heated in a Water bath with 40 ml. of acetic anhydride for 15 hours. The batch is then rapidly evaporated under a water-jet vacuum. The residue is dissolved in chloroform and the solution extracted by shaking first with aqueous sodium bicarbonate solution and then with water before it is dried over sodium sulfate.
• the base is dissolved in a small amount of ethanol, neutralized with hydrogen chloride in ethyl acetate, and diluted with ether.
• the 1-phenyl-3-(cyclopropylmethyl)- 5 ,8 acetoxy 2:3:4r5-tetrahydro-1:4-methano-1H-3-benzazepine hydrochloride crystallizes in colorless needless melting at 171 to 173 C.
• Example 70 A solution of 9.5 g. (0.04 mol) of l-phenyl-2:3:4:5 tetrahydro 1:4-methano-1H-3-benzazepine in 200 ml. of isopropanol is treated with potassium carbonate and then, while stirring and cooling with ice, with 5.4 g. (0.44 mol) of allyl bromide. The batch is allowed to react for 1 hour at room temperature, then refluxed for 12 hours. After cooling, the inorganic matter is eliminated by filtration, and the filtrate evaporated. The residue is dissolved in chloroform and the solution thoroughly extracted by agitation with water. The extract is dried over sodium sulfate and the oil that remains behind distilled in a high vacuum.
• the 1 phenyl 3 allyl 2:3:4:5 tetrahydro l:4-methano-lH-3-benzazepine of the formula is a colorless oil boiling at 143 to 150 C. under a pressure of 0.05 mm. Hg.
• Example 71 At 20 C. a solution of 3.91 g. (0.0375 mol) of cyclopropanecarboxylic acid chloride in 25 ml. of methylene chloride is added dropwise to a solution of 8.0 g. (0.034 mol) of 1 phenyl 2:3 :4:5 tetrahydro 1:4 methanolH-3-benzazepine and 7 ml. of triethylamine in 2.00 ml. of methylene chloride. The solution is heated in a water bath for 30 minutes, then cooled, and extracted by agitation with 50 ml. of 2 N-hydrochloric acid and with 2X50 ml. of water. The residue is dissolved in ml.
• Example 72 A solution of 21.7 g. (0.1 mol) of 1-ethyl-3-methyl- 56 hydroxy 2:3:4:5 tetrahydro 1:4 methano 1H- 3-benzazepine in 1 00 ml. of benzene is treated with 14.2 g. (0.2 mol) of ethylisocyanate and with exclusion of moisture, refluxed for 15 hours. Rapid evaporation under a water-jet vacuum yields the 1-ethyl-3-methyl-5B-(ethylcarbamoyloxy) 2:3:4:5 tetrahydro-1:4-methano-1H-3- benzazepine of the formula in the form of a viscous, colorless oil. The base is dissolved in acetone and the solution neutralized with hydrogen chloride in ethyl acetane to obtain the hydrochloride: colorless crystals of melting point 187 to 190 C.
• Example 73 A solution of 11.75 g. (0.05 mol) of l-phenyl-2:3:4:5- tetrahydro-l:4-methano-lH-3-benzazepine in 100 ml. of 98.5% formic acid is heated for 2 hours on -a boiling water bath with 4.8 ml. of 40% formalin (0.06 mol). The solution is evaporated under reduced pressure, the residue dissolved in 150 ml. of methylene chloride, and the solution extracted, first with 100 ml. of N-sodium hydroxide solution, and then with 2X5 ml. of Water. The methylene chloride solution is dried over sodium sulfate and the sol-vent evaporated.
• Example 74 18.7 g. of (0.1 mol) of 1-ethyl-2:3z4z5-tetrahydro-lz4- methano-lH-3-benzazepine in 200 ml. of isopropanol are refluxed for 15 hours with vigorous stirring together with 50 g. of finely powdered potassium carbonate and 18.5 g. (0.1 mol) of B-phenylethylbromide. After cooling, the batch is filtered with the filtrate evaporated. The residue is heated for a short while with 50 ml. of acetic anhydride and the solution then evaporated.
• Example 75 7.7 g. (0.033 ml.) of 1-ethyl-3-methyl-8-methoxy- 2:3:4:5 tetrahydro-l:4-methano-1H-3-benzazepine are heated at 120 C. for 15 hours in a 33% solution of hydrogen bromide in glacial acetic acid. The batch is rapidly evaporated under reduced pressure, and the reaction performed once more. The red reaction product is dissolved in 30 m1. of hot water, treated with active carbon, and filtered.
• the 1 ethyl 3 methyl 8 hydroxy 2:314:5- tetrahydro-l:4-methano-1H-3-benzazepine hydrochloride crystallizes from aqueous acetone only after being allowed to stand for several days. Beige-colored crystals melting at 230 to 235 C.
• Example 76 2.17 g. (0.01 mol) of 1-ethyl-3-methyl-8-hydroxy- 2:3:4:5 tetrahydro 1:4 methano 1H 3 benzazepine are heated on a boiling water bath for 3 hours with 2 ml. of pyridine and 20 ml. of acetic anhydride. The batch is evaporated under a water-jet vacuum, the residue dissolved in chloroform, and the solution extracted by agitation with aqueous ammonia solution and then with water. The chloroformic solution is dried and evaporated under reduced pressure, and the oil which remains behind neutralized in acetone with a solution of hydrogen chloride in ethyl acetate.
• Example 77 While stirring, 14.5 g. (0.1 mol) of phenylacetyl chloride are added dropwise to a solution of 21.7 g. (0.1 mol) of 1 ethyl 8 methoxy-2:3:4z5-tetrahydro-1:4- methano-1H-3-benzazepine in 15 ml. of triethylamine and 200 ml. of methylene chloride. The solution boils spontaneously. It is allowed to cool and then extracted by agitation with 50 ml. of N-hydrochloric acid and 2X50 ml. of water. The methylene chloride solution is dried over sodium sulfate before it is evaporated under reduced pressure. 32.7 g.
• the 1-ethyl-3-(fl-phenylethyl) 8 methoxy-2:3:4:5-tetrahydro-1:4-methano-1H 3 benzazepine hydrochloride crystallizes in colorless cubes of melting point to 196 C.
• the 1- ethyl 3 s-phenylethyl)-8-hydroxy-2:3:4z5-tetrahydro- 1:4-methano-1H-3-benzazepine of the formula CgHs then crystallizes. Suction filtering and crystallization from a. mixture of ethyl acetate and ether yield beige-colored crystals of melting point 169 to 171 C.
• Example 79 At C. a solution of 37.2 g. (0.1 mol) of l-ethyl- 3 bromo 4 oxo 1:2:3:4 tetrahydronaphthalene 1- carboxylic acid anilide in 150 ml. of absolute methanol are added dropwise to a solution of 9.2 g. (0.4 mol) of sodium in 150 ml. of absolute methanol. The reaction mixture heats up to C. It is stirred for 1 hour, then slightly acidified by the addition of 160 ml. of 2 N-hydrochloric acid. The mixture is diluted with 300 m1. of water and extracted with chloroform. The oily product obtained is dissolved in ml. of benzene and the solution filtered through 500 g.
• the 1 ethyl 3 bromo 4 oxo 1:2:3 :4 tetrahydronaphthalene-l-carboxylic acid anilide used as starting material can be obtained as follows:
• Example 80 Tablets containing 10 mg. of 1-phenyl-3-methyl- 2 3 :4:5-tetrahydro-1 :4-methano-1H-3-benzazepine methsulfonate and having the following composition can be prepared:
• the 1 phenyl 3 methyl 2:3:4:5 tetrahydro- 1:4-methano-1H-3-benzazepine methanesulfonate is mixed with part of the wheat starch, and with lactose and colloidal silicic acid, and the mixture forced through a sieve.
• the remainder of the wheat starch is pasted on a water bath with the five-fold quantity of water, and the paste kneaded with the powder mixture until a slightly plastic mass is obtained.
• the plastic mass is pressed through a sieve having a mesh width of 3 mm., then dried, and the dry granulate forced through a sieve.
• Arrowroot, talc and magnesium stearate are then admixed and the resulting mixture compressed into tablets weighing mg. each.
• R stands for lower alkyl, R for lower alkyl and R for lower alkanoyloxy and acid addition salts thereof.
• R stands for lower alkyl and R for a member selected from the group consisting of lower alkyl, lower alkenyl, cyclo-lower alkyl-lower alkyl and phenyl-lower alkyl, and acid addition salts thereof.
• R stands for a member selected from the group consisting of hydrogen, lower alkyl, phenyl, (lower alkyl)- phenyl, (lower -alkoXy)-phenyl, (ha logeno)-phenyl, (trifluoromethyl)-phenyl, phenyl-lower alkyl, (lower alkyl)- phenyl-lower alkyl, (lower alkoXy)-phenyl-'lower alkyl, (halogeno)-phenyl-lower alkyl and (trifluoromethyD- phenyl-lower alkyl, R for a member selected from the group consisting of hydrogen, lower alkyl, cyclo-lower alkyl, cycle-lower alkyl-lower alkyl, lower alkenyl, phenyl, (lower alkyl)-phenyl, (lower alk
• NICHOLAS S. RIZZO Primary Examiner.

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  • 1965-05-21 US US457858A patent/US3396171A/en not_active Expired - Lifetime
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